Despite epidemiological evidence linking dietary calcium and vitamin D to prostate cancer risk, the limited availability of basic and pre-clinical research precludes the development of specific recommendations regarding intake of these nutrients for men at risk of prostate cancer or those living with the disease. Men with prostate cancer may self medicate or seek complementary and alternative medicines, including calcium or vitamin D supplements, however the impact of such practises on disease progression or response to therapy is unknown. In the proposed studies, we will use transgenic, knockout and xenograft animal models to test the hypothesis is that the vitamin D receptor represents a nutritionally modulated growth regulatory gene in prostate. 1,25D, the ligand for the VDR which is derived from vitamin D, induces growth arrest, differentiation and apoptosis in normal and transformed prostate cells. Since dietary calcium is the major determinant of circulating 1,25D, a corollary to this hypothesis is that calcium consumption will indirectly affect prostate cancer via modulation of the vitamin D endocrine system. Three specific aims have been designed to test this hypothesis: Aim 1. To determine whether alterations in dietary calcium or VDR signaling can prevent prostate tumorigenesis in a transgenic mouse model. Aim 2. To assess the impact of dietary calcium and a vitamin D analog on progression of early stage human prostate cancer. Aim 3. To identify cellular targets for calcium and VDR modulation of prostate tumorigenesis. In Aim 1 and 2, we will comprehensively evaluate the effects of dietary calcium and vitamin D status on prostate tumor initiation, progression and metastasis and response to anti-androgen therapy. The experiments in Aim 3 will identity gene targets and provide mechanistic understanding of the role of redox signaling in modulating the effects of dietary calcium and vitamin D on normal prostate biology, tumor initiation, local and metastatic progression. These studies are highly responsive to RFA #CA-03-003, Molecular Targets for Nutrients in Prostate Cancer Prevention, and have the potential to impact on dietary recommendations for men at risk for prostate cancer or those living with the disease.